Quantitative Assessment of Condylar Remodeling After Open Reduction and Internal Fixation in Mandibular Condylar Head Fractures.

Open reduction and internal fixation (OR/IF) and closed treatments are viable options, with OR/IF gaining popularity in mandibular condylar head fracture (CHF). Sufficient research is lacking on long-term condylar morphologic changes. This study quantitatively evaluated the morphologic changes in the condylar head in patients who underwent OR/IF for CHF without the removal of osteosynthesis material. A retrospective study analyzed patients who underwent OR/IF for CHF between November 2010 and August 2022. The transverse/lateral condyle width and condyle height were radiologically analyzed using panoramic and reverse Towne view x-ray images at immediate (T0), short-term (T1), and long-term (T2) postoperative periods. The study involved 29 patients with 32 surgically treated CHF. Long-term condyle height decreased significantly from 18.9±0.8 mm at T0 to 18.1±0.8 mm at T1 (P=0.042), and further to 17.3±0.7 mm at T2 (P=0.034). Transverse width slightly reduced from 18.7±0.7 mm at T0 to 17.9±0.8 mm at T1 (P=0.001) but remained stable from T1 to T2 (17.6±1.0 mm, P=0.756). Following surgery, maximal mouth opening averaged 39.5±6.1 mm, with one case of chin deviation and three cases of joint pain. The condyle undergoes long-term shortening without altering its width. Nevertheless, patients experience favorable functional outcomes, including satisfactory mouth opening and occlusion. In addition, it is advisable not to remove the osteosynthesis material, as the remaining material causes minimal functional impairment and bone resorption.

Phospholipid transfer function of PTPIP51 at mitochondria-associated ER membranes.

In eukaryotic cells, mitochondria are closely tethered to the endoplasmic reticulum (ER) at sites called mitochondria-associated ER membranes (MAMs). Ca2+ ion and phospholipid transfer occurs at MAMs to support diverse cellular functions. Unlike those in yeast, the protein complexes involved in phospholipid transfer at MAMs in humans have not been identified. Here, we determine the crystal structure of the tetratricopeptide repeat domain of PTPIP51 (PTPIP51_TPR), a mitochondrial protein that interacts with the ER-anchored VAPB protein at MAMs. The structure of PTPIP51_TPR shows an archetypal TPR fold, and an electron density map corresponding to an unidentified lipid-like molecule probably derived from the protein expression host is found in the structure. We reveal functions of PTPIP51 in phospholipid binding/transfer, particularly of phosphatidic acid, in vitro. Depletion of PTPIP51 in cells reduces the mitochondrial cardiolipin level. Additionally, we confirm that the PTPIP51-VAPB interaction is mediated by the FFAT-like motif of PTPIP51 and the MSP domain of VAPB. Our findings suggest that PTPIP51 is a phospholipid transfer protein with a MAM-tethering function.

An Analysis of the Demographics and Clinical Characteristics of Transgender and Intersex Populations in Korea: A Retrospective Study Using HIRA Database.

BACKGROUND: Transgender and intersex populations have long remained under-documented in South Korea, largely due to the absence of comprehensive epidemiological data. With increasing societal acknowledgment, there's an urgent need to understand the demographics and health challenges faced by these communities. METHODS: This retrospective, large-scale data study included people who received the F64 codes from the Korean Health Insurance Review & Assessment Service between January 2007 and December 2021. Demographics, gender-affirmative treatments, and psychiatric related medications were examined. RESULTS: Between 2007 and 2021, 8,602 patients were diagnosed with "gender identity disorder" and 45 with "intersex." A steadily increasing annual prevalence was observed, peaking at 986 cases in 2021. The majority (79.8%) were aged between 10 and 30. Nearly half (53.2%) exhibited mental and behavioral disorders. Two-thirds had been prescribed anxiolytics or sedatives either before or after diagnosis. Merely 12.1% received hormone therapy covered by health insurance. CONCLUSION: This is the first large-scale study highlighting the demographics and clinical characteristics of the transgender and intersex populations in Korea. The study reveals a consistent growth of these communities over the past 15 years, with a significant proportion under 30 years of age facing mental and behavioral challenges. Findings underscore the need for targeted healthcare interventions, early psychological support, and comprehensive insurance coverage tailored to the specific needs of these individuals in Korea.

The structure of Deinococcus radiodurans transcriptional regulator HucR retold with the urate bound.

HucR is a MarR family protein of Deinococcus radiodurans, which binds tightly to the intergenic region of HucR and the uricase gene to inhibit their expression. Urate (or uric acid) antagonizes the repressor function of HucR by binding to HucR to impede its association with the cognate DNA. The previously reported crystal structure of HucR was without the bound urate showing significant structural homology to other MarR structures. In this paper, we report the crystal structure of HucR determined with the urate bound. However, despite the fact that the urate is found at a site well-known to harbor ligands in other MarR family proteins, the overall HucR structure indicates that no significant change in structure takes place with the urate bound. Structure analysis further suggests that the urate interaction in HucR is mediated by histidine/glutamate side chains and ordered water molecules stabilized by various residues. Such interaction is quite unique compared to other known structural interactions between urate and its binding proteins. Furthermore, structural comparison of the apo- and the urate bound forms allows us to hypothesize that the Trp20-mediated water network in the apo-form stabilizes the proper HucR fold for cognate DNA binding, and that urate binding, also via Trp20, and the consequent reorganization of water molecules in the binding pocket, likely disrupts the DNA binding configuration to result in the attenuated DNA binding.

Regulation of mRNA export through API5 and nuclear FGF2 interaction.

API5 (APoptosis Inhibitor 5) and nuclear FGF2 (Fibroblast Growth Factor 2) are upregulated in various human cancers and are correlated with poor prognosis. Although their physical interaction has been identified, the function related to the resulting complex is unknown. Here, we determined the crystal structure of the API5-FGF2 complex and identified critical residues driving the protein interaction. These findings provided a structural basis for the nuclear localization of the FGF2 isoform lacking a canonical nuclear localization signal and identified a cryptic nuclear localization sequence in FGF2. The interaction between API5 and FGF2 was important for mRNA nuclear export through both the TREX and eIF4E/LRPPRC mRNA export complexes, thus regulating the export of bulk mRNA and specific mRNAs containing eIF4E sensitivity elements, such as c-MYC and cyclin D1. These data show the newly identified molecular function of API5 and nuclear FGF2, and provide a clue to understanding the dynamic regulation of mRNA export.

The Reciprocal Interaction Between Sleep and Alzheimer's Disease.

It is becoming increasingly recognized that patients with a variety of neurodegenerative diseases exhibit disordered sleep/wake patterns. While sleep impairments have typically been thought of as sequelae of underlying neurodegenerative processes in sleep-wake cycle regulating brain regions, including the brainstem, hypothalamus, and basal forebrain, emerging evidence now indicates that sleep deficits may also act as pathophysiological drivers of brain-wide disease progression. Specifically, recent work has indicated that impaired sleep can impact on neuronal activity, brain clearance mechanisms, pathological build-up of proteins, and inflammation. Altered sleep patterns may therefore be novel (potentially reversible) dynamic functional markers of proteinopathies and modifiable targets for early therapeutic intervention using non-invasive stimulation and behavioral techniques. Here we highlight research describing a potentially reciprocal interaction between impaired sleep and circadian patterns and the accumulation of pathological signs and features in Alzheimer's disease, the most prevalent neurodegenerative disease in the elderly.

Synthesis and Structure-Activity Relationships of Aristoyagonine Derivatives as Brd4 Bromodomain Inhibitors with X-ray Co-Crystal Research.

Epigenetic regulation is known to play a key role in progression of anti-cancer therapeutics. Lysine acetylation is an important mechanism in controlling gene expression. There has been increasing interest in bromodomain owing to its ability to modulate transcription of various genes as an epigenetic 'reader.' Herein, we report the design, synthesis, and X-ray studies of novel aristoyagonine (benzo[6,7]oxepino[4,3,2-cd]isoindol-2(1H)-one) derivatives and investigate their inhibitory effect against Brd4 bromodomain. Five compounds 8ab, 8bc, 8bd, 8be, and 8bf have been discovered with high binding affinity over the Brd4 protein. Co-crystal structures of these five inhibitors with human Brd4 bromodomain demonstrated that it has a key binding mode occupying the hydrophobic pocket, which is known to be the acetylated lysine binding site. These novel Brd4 bromodomain inhibitors demonstrated impressive inhibitory activity and mode of action for the treatment of cancer diseases.

Predictors affecting complications and aesthetic outcomes in autologous breast reconstruction with free muscle-sparing transverse rectus abdominis myocutaneous flaps.

BACKGROUND: Identification and understanding of predictors for complications and aesthetic outcomes in free muscle-sparing transverse rectus abdominis myocutaneous (MS-TRAM) flap are essential for successful breast reconstruction. The purpose of this study was to investigate predictors for complications and aesthetic outcomes in patients who underwent autologous breast reconstruction with free MS-TRAM flaps. PATIENTS AND METHODS: Between March 2003 and September 2017, a total of 214 patients who underwent breast reconstruction with MS-TRAM flaps were included in this study. Mean age of the patients was 43.2 years (range, 28-61 years). Four outcome data, including operation time, hospital stay, aesthetic scores, and complications; and 12 patient data, including recipient vessel type, age, body mass index [BMI] > 25, smoking status, neoadjuvant chemotherapy, radiotherapy, nipple-sparing mastectomy, contralateral breast surgery, history of hypertension, diabetes mellitus, cardiac disease, and endocrine disease were collected. RESULTS: Five and 52 patients experienced major complications, including partial flap loss, and minor complications, respectively. In stepwise multiple logistic analysis, risk factors for complications were BMI > 25 (P < 0.001), smoking status (P = 0.012), and neoadjuvant radiotherapy (P = 0.002). BMI > 25 (P < 0.001), smoking status (P < 0.001), contralateral breast surgery (P < 0.001), and history of cardiac (P = 0.001) and endocrine disease (P = 0.003) were predictors for aesthetic outcome. CONCLUSION: Predictors for complications and aesthetic outcomes determined in this study may facilitate microsurgeons engaged in the assessment of patients needing free MS-TRAM flaps.

Comparison of the Outcomes of Closed Reduction Nasal Bone Fractures With a Surgical Navigation System.

BACKGROUND: The most prevalent form of facial bone fractures is nasal fractures. The surgical procedures used for these fractures are relatively simple, but complete correction is not easy because the nasal bone is small and identifying the fracture site by palpation is difficult. This study aimed to investigate the efficacy of intraoperative surgical navigation systems in nasal bone fracture surgery through a prospective analysis. METHODS: Between February 2019 and July 2019, 25 navigation-assisted closed reductions of nasal fractures were performed. Preoperative computed tomography images were obtained at 1-mm intervals before surgery and the navigation was set by a simulation to have an error rate of less than 1. Then, the navigation system was used to identify the fracture site. Closed reduction was performed with Asch forceps and a Langenbeck elevator based on the previous markings made using the navigation system. RESULTS: The degree of reduction was evaluated by plain X-rays and computed tomography scans, which were performed 1 month after surgery. In the navigation group, the average distance between the fragment and normal bony alignment was decreased from 2.38 to 0.49 mm and the modified Motomura score was an average of 2.40 points. The decrease in the mean distance was significantly different (P = 0.038) compared with the conventional group. CONCLUSIONS: Surgical navigation systems could be a useful tool for localizing fracture sites and guiding closed reductions. In particular, the system could be recommended for nasal bone fracture reductions in the tip or pyriform regions, which are difficult to correct. LEVEL OF EVIDENCE: II.

Crystal Structure of the Kinase Domain of MerTK in Complex with AZD7762 Provides Clues for Structure-Based Drug Development.

Aberrant tyrosine-protein kinase Mer (MerTK) expression triggers prosurvival signaling and contributes to cell survival, invasive motility, and chemoresistance in many kinds of cancers. In addition, recent reports suggested that MerTK could be a primary target for abnormal platelet aggregation. Consequently, MerTK inhibitors may promote cancer cell death, sensitize cells to chemotherapy, and act as new antiplatelet agents. We screened an inhouse chemical library to discover novel small-molecule MerTK inhibitors, and identified AZD7762, which is known as a checkpoint-kinase (Chk) inhibitor. The inhibition of MerTK by AZD7762 was validated using an in vitro homogeneous time-resolved fluorescence (HTRF) assay and through monitoring the decrease in phosphorylated MerTK in two lung cancer cell lines. We also determined the crystal structure of the MerTK:AZD7762 complex and revealed the binding mode of AZD7762 to MerTK. Structural information from the MerTK:AZD7762 complex and its comparison with other MerTK:inhibitor structures gave us new insights for optimizing the development of inhibitors targeting MerTK.

Apoptosis inhibitor 5 is an endogenous inhibitor of caspase-2.

Caspases are key enzymes responsible for mediating apoptotic cell death. Across species, caspase-2 is the most conserved caspase and stands out due to unique features. Apart from cell death, caspase-2 also regulates autophagy, genomic stability and ageing. Caspase-2 requires dimerization for its activation which is primarily accomplished by recruitment to high molecular weight protein complexes in cells. Here, we demonstrate that apoptosis inhibitor 5 (API5/AAC11) is an endogenous and direct inhibitor of caspase-2. API5 protein directly binds to the caspase recruitment domain (CARD) of caspase-2 and impedes dimerization and activation of caspase-2. Interestingly, recombinant API5 directly inhibits full length but not processed caspase-2. Depletion of endogenous API5 leads to an increase in caspase-2 dimerization and activation. Consistently, loss of API5 sensitizes cells to caspase-2-dependent apoptotic cell death. These results establish API5/AAC-11 as a direct inhibitor of caspase-2 and shed further light onto mechanisms driving the activation of this poorly understood caspase.

The Influence of Dissection Range of the Facial Nerve on Transient Postoperative Facial Palsy in Mandibular Condyle Fractures.

PURPOSE: This study examined the relation between dissection range of facial nerve branches and transient postoperative facial palsy caused by nerve traction for open treatment of mandibular condyle fractures using a preauricular approach. MATERIALS AND METHODS: This retrospective study included 58 patients who underwent rigid fixation of condylar head and upper neck fractures. Patients were divided into 3 groups based on dissection range of the frontal and zygomatic branches. For group 1 (n = 22), the dissection range was extended anteriorly and posteriorly from the condylar borders through the retroparotid approach. The transparotid approach was used in groups 2 (n = 19) and 3 (n = 17) in which nerve dissection was limited to the condylar borders and was extended only anteriorly, respectively. Using multivariate correlation and multiple regression analyses, differences in duration of nerve traction and angle difference by traction from the natural course of the nerve were analyzed according to dissection range, and the recovery period for facial palsy was evaluated. RESULTS: The duration of nerve traction for group 2 was 77.53 minutes, which was longer than that for groups 1 (66.00 minutes) and 3 (65.41 minutes). The angle differences by traction were 62.42° and 58.00° for the frontal and zygomatic branches in group 2, respectively, which were considerably greater than those in groups 1 (23.32° and 20.14°) and 3 (37.24° and 28.88°). In consequence, group 2 showed the longest recovery, requiring 64.47 days for the frontal branch and 51.63 days for the zygomatic branch. The angle difference by traction had a greater influence on the recovery period than duration of nerve traction. CONCLUSIONS: Duration of nerve traction and angle difference by traction were quantitatively dependent on the dissection range of facial nerve branches and were related to the recovery period for transient facial palsy.

Sporadic Early-Onset Diffuse Gastric Cancers Have High Frequency of Somatic CDH1 Alterations, but Low Frequency of Somatic RHOA Mutations Compared With Late-Onset Cancers.

BACKGROUND & AIMS: Early-onset gastric cancer, which develops in patients younger than most gastric cancers, is usually detected at advanced stages, has diffuse histologic features, and occurs more frequently in women. We investigated somatic genomic alterations associated with the unique characteristics of sporadic diffuse gastric cancers (DGCs) from younger patients. METHODS: We conducted whole exome and RNA sequence analyses of 80 resected DGC samples from patients 45 years old or younger in Korea. Patients with pathogenic germline mutations in CDH1, TP53, and ATM were excluded from the onset of this analysis, given our focus on somatic alterations. We used MutSig2CV to evaluate the significance of mutated genes. We recruited 29 additional early-onset Korean DGC samples and performed SNP6.0 array and targeted sequencing analyses of these 109 early-onset DGC samples (54.1% female, median age, 38 years). We compared the SNP6.0 array and targeted sequencing data of the 109 early-onset DGC samples with those from diffuse-type stomach tumor samples collected from 115 patients in Korea who were 46 years or older (late onset) at the time of diagnosis (controls; 29.6% female, median age, 67 years). We compared patient survival times among tumors from different subgroups and with different somatic mutations. We performed gene silencing of RHOA or CDH1 in DGC cells with small interfering RNAs for cell-based assays. RESULTS: We identified somatic mutations in the following genes in a significant number of early-onset DGCs: the cadherin 1 gene (CDH1), TP53, ARID1A, KRAS, PIK3CA, ERBB3, TGFBR1, FBXW7, RHOA, and MAP2K1. None of 109 early-onset DGC cases had pathogenic germline CDH1 mutations. A higher proportion of early-onset DGCs had mutations in CDH1 (42.2%) or TGFBR1 (7.3%) compared with control DGCs (17.4% and 0.9%, respectively) (P < .001 and P = .014 for CDH1 and TGFBR1, respectively). In contrast, a smaller proportion of early-onset DGCs contained mutations in RHOA (9.2%) than control DGCs (19.1%) (P = .033). Late-onset DGCs in The Cancer Genome Atlas also contained less frequent mutations in CDH1 and TGFBR1 and more frequent RHOA mutations, compared with early-onset DGCs. Early-onset DGCs from women contained significantly more mutations in CDH1 or TGFBR1 than early-onset DGCs from men. CDH1 alterations, but not RHOA mutations, were associated with shorter survival times in patients with early-onset DGCs (hazard ratio, 3.4; 95% confidence interval, 1.5-7.7). RHOA activity was reduced by an R5W substitution-the RHOA mutation most frequently detected in early-onset DGCs. Silencing of CDH1, but not RHOA, increased migratory activity of DGC cells. CONCLUSIONS: In an integrative genomic analysis, we found higher proportions of early-onset DGCs to contain somatic mutations in CDH1 or TGFBR1 compared with late-onset DGCs. However, a smaller proportion of early-onset DGCs contained somatic mutations in RHOA than late-onset DGCs. CDH1 alterations, but not RHOA mutations, were associated with shorter survival times of patients, which might account for the aggressive clinical course of early-onset gastric cancer. Female predominance in early-onset gastric cancer may be related to relatively high rates of somatic CDH1 and TGFBR1 mutations in this population.

Structural and biochemical insights into the role of testis-expressed gene 14 (TEX14) in forming the stable intercellular bridges of germ cells.

Intercellular bridges are a conserved feature of spermatogenesis in mammalian germ cells and derive from arresting cell abscission at the final stage of cytokinesis. However, it remains to be fully understood how germ cell abscission is arrested in the presence of general cytokinesis components. The TEX14 (testis-expressed gene 14) protein is recruited to the midbody and plays a key role in the inactivation of germ cell abscission. To gain insights into the structural organization of TEX14 at the midbody, we have determined the crystal structures of the EABR [endosomal sorting complex required for transport (ESCRT) and ALIX-binding region] of CEP55 bound to the TEX14 peptide (or its chimeric peptides) and performed functional characterization of the CEP55-TEX14 interaction by multiexperiment analyses. We show that TEX14 interacts with CEP55-EABR via its AxGPPx3Y (Ala793, Gly795, Pro796, Pro797, and Tyr801) and PP (Pro803 and Pro804) sequences, which together form the AxGPPx3YxPP motif. TEX14 competitively binds to CEP55-EABR to prevent the recruitment of ALIX, which is a component of the ESCRT machinery with the AxGPPx3Y motif. We also demonstrate that a high affinity and a low dissociation rate of TEX14 to CEP55, and an increase in the local concentration of TEX14, cooperatively prevent ALIX from recruiting ESCRT complexes to the midbody. The action mechanism of TEX14 suggests a scheme of how to inactivate the abscission of abnormal cells, including cancer cells.

Carbon Nanodot-Sensitized Modulation of Alzheimer's ß-Amyloid Self-Assembly, Disassembly, and Toxicity.

The self-assembly of amyloidogenic peptides into ß-sheet-rich aggregates is a general feature of many neurodegenerative diseases, including Alzheimer's disease, which signifies the need for the effective attenuation of amyloid aggregation toward alleviating amyloid-associated neurotoxicity. This study reports that photoluminescent carbon nanodots (CDs) can effectively suppress Alzheimer's ß-amyloid (Aß) self-assembly and function as a ß-sheet breaker disintegrating preformed Aß aggregates. This study synthesizes CDs using ammonium citrate through one-pot hydrothermal treatment and passivates their surface with branched polyethylenimine (bPEI). The bPEI-coated CDs (bPEI@CDs) exhibit hydrophilic and cationic surface characteristics, which interact with the negatively charged residues of Aß peptides, suppressing the aggregation of Aß peptides. Under light illumination, bPEI@CDs display a more pronounced effect on Aß aggregation and on the dissociation of ß-sheet-rich assemblies through the generation of reactive oxygen species from photoactivated bPEI@CDs. The light-triggered attenuation effect of Aß aggregation using a series of experiments, including photochemical and microscopic analysis, is verified. Furthermore, the cell viability test confirms the ability of photoactivated bPEI@CDs for the suppression of Aß-mediated cytotoxicity, indicating bPEI@CDs' potency as an effective anti-Aß neurotoxin agent.

Rattle-Structured Upconversion Nanoparticles for Near-IR-Induced Suppression of Alzheimer's ß-Amyloid Aggregation.

Rose bengal (RB)-loaded upconverting nanocomposites are synthesized as a near-infrared (NIR)-responsive inhibitor of Aß aggregation. Rattle-structured, organosilica shell (ROS) is deposited on NaYF4 :Yb,Er nanocrystals (UCNPs) for high loading efficiency and disaggregation of RB. RB/UCNP@ROS successfully inhibits Aß self-assembly under NIR irradiation by generating 1 O2 . Furthermore, photoexcited RB/UCNP@ROS is effective in suppressing Aß-induced cytotoxicity.

The Cell Shape-determining Csd6 Protein from Helicobacter pylori Constitutes a New Family of L,D-Carboxypeptidase.

Helicobacter pylori causes gastrointestinal diseases, including gastric cancer. Its high motility in the viscous gastric mucosa facilitates colonization of the human stomach and depends on the helical cell shape and the flagella. In H. pylori, Csd6 is one of the cell shape-determining proteins that play key roles in alteration of cross-linking or by trimming of peptidoglycan muropeptides. Csd6 is also involved in deglycosylation of the flagellar protein FlaA. To better understand its function, biochemical, biophysical, and structural characterizations were carried out. We show that Csd6 has a three-domain architecture and exists as a dimer in solution. The N-terminal domain plays a key role in dimerization. The middle catalytic domain resembles those of l,d-transpeptidases, but its pocket-shaped active site is uniquely defined by the four loops I to IV, among which loops I and III show the most distinct variations from the known l,d-transpeptidases. Mass analyses confirm that Csd6 functions only as an l,d-carboxypeptidase and not as an l,d-transpeptidase. The d-Ala-complexed structure suggests possible binding modes of both the substrate and product to the catalytic domain. The C-terminal nuclear transport factor 2-like domain possesses a deep pocket for possible binding of pseudaminic acid, and in silico docking supports its role in deglycosylation of flagellin. On the basis of these findings, it is proposed that H. pylori Csd6 and its homologs constitute a new family of l,d-carboxypeptidase. This work provides insights into the function of Csd6 in regulating the helical cell shape and motility of H. pylori.

Structure of Csd3 from Helicobacter pylori, a cell shape-determining metallopeptidase.

Helicobacter pylori is associated with various gastrointestinal diseases such as gastritis, ulcers and gastric cancer. Its colonization of the human gastric mucosa requires high motility, which depends on its helical cell shape. Seven cell shape-determining genes (csd1, csd2, csd3/hdpA, ccmA, csd4, csd5 and csd6) have been identified in H. pylori. Their proteins play key roles in determining the cell shape through modifications of the cell-wall peptidoglycan by the alteration of cross-linking or by the trimming of peptidoglycan muropeptides. Among them, Csd3 (also known as HdpA) is a bifunctional enzyme. Its D,D-endopeptidase activity cleaves the D-Ala(4)-mDAP(3) peptide bond between cross-linked muramyl tetrapeptides and pentapeptides. It is also a D,D-carboxypeptidase that cleaves off the terminal D-Ala(5) from the muramyl pentapeptide. Here, the crystal structure of this protein has been determined, revealing the organization of its three domains in a latent and inactive state. The N-terminal domain 1 and the core of domain 2 share the same fold despite a very low level of sequence identity, and their surface-charge distributions are different. The C-terminal LytM domain contains the catalytic site with a Zn(2+) ion, like the similar domains of other M23 metallopeptidases. Domain 1 occludes the active site of the LytM domain. The core of domain 2 is held against the LytM domain by the C-terminal tail region that protrudes from the LytM domain.

Highly potent and selective pyrazolylpyrimidines as Syk kinase inhibitors.

A series of pyrazolylpyrimidine scaffold based Syk inhibitors were synthesized and evaluated for their biological activities and selectivity. Lead optimization efforts provided compounds with potent Syk inhibition in both enzymatic and TNF-α release assay.

Vascularized Partial Free Toe Tissue Transfer Under Local Anesthesia.

BACKGROUND: This study was designed to introduce free toe soft tissue transfer using local infiltration anesthesia in patients not suitable for general anesthesia and local tissue coverage. METHODS: From January 2006 to August 2012, a total of 11 traumatic fingertip defects were reconstructed by toe soft tissue transfer. All procedures except 1 were done as primary reconstructions, with either the lateral side of the great toe (5 cases) or the medial side of the second toe (6 cases) used as a donor. Postoperative follow-up periods were between 8 months to 2 years and 6 months. RESULTS: Flap sizes varied from 1.0 × 2.0 to 2.0 × 3.5 cm. The mean operative times were 4 hours 29 minutes for cases done by a single team and 3 hours 21 minutes for cases done by a 2-team approach. Approximately 5.8 mL of local anesthetic agent was used in each finger and 5.9 mL was used in the toes for a total of 11.7 mL. All flaps survived and were fully taken without complications, except 1 case that presented partial necrosis. CONCLUSIONS: Fingertip soft tissue reconstruction by free toe tissue transfer under local anesthesia uses a more limited operative field, with a shorter operative time, enabling reconstruction in patients not suitable for general anesthesia. This is even more so with a microsurgical 2-team approach, which reduces the volume of anesthetic agent needed, making this method a sufficiently realistic option for fingertip soft tissue reconstruction.